L723P
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialLeucine → Proline at position 723 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.959, DynaMut2 ΔΔG -0.19 kcal/mol (destabilising). Another proline-introduction variant in the lumenal fold.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I720 | I720 | Preserved |
| Polar contact | — | A719 | Gained |
| Polar contact | I720 | I720 | Preserved |
| Van der Waals | — | I720 | Gained |
| Van der Waals | N721 | — | Lost |
| Hydrophobic | I727 | I727 | Preserved |
| Hydrophobic | M731 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 723 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L723 within 5 Å of MET722 (2.5 Å), PRO724 (2.5 Å), ILE720 (3.6 Å), ASN721 (4.6 Å), and ALA719 (4.8 Å). The local environment is hydrophobic-rich (M722, I720, A719) with a single polar residue (N721). Notably, PRO724 sits at 2.5 Å — the immediate downstream neighbor is already a proline.
Replacing L723 with proline introduces a second proline immediately adjacent to the existing P724 — a Pro-Pro motif is unusual and structurally distinctive. Two adjacent prolines create a particularly rigid backbone segment with restricted conformational options. The wild-type Leu-Pro motif at 723-724 transitions from flexible to constrained backbone; the variant Pro-Pro motif is constrained on both sides.
The |ΔΔG| of 0.19 is modest — the fold absorbs the new proline because the local environment was already constrained. But the geometry shifts: the Pro-Pro motif likely adopts a different local conformation than the wild-type Leu-Pro, and surrounding residues (M722, I720) rearrange to accommodate.
AlphaMissense's 0.959 score captures the functional severity — the shifted local geometry disrupts whatever interaction the wild-type Leu-Pro motif enabled.
Druggability Assessment
The mechanism is creation of an unusual Pro-Pro motif at positions 723-724, shifting the local backbone geometry from a Leu-Pro transition to a rigid Pro-Pro segment. Therapeutic strategy: site-directed small molecules at the position 720-724 region, ideally compensating for the geometric shift.
This is one of several proline-introduction variants in the Atlas (L402P, L543P, L723P, L804P). The therapeutic vocabulary across this class is consistent: stabilize local backbone geometry against the introduced proline kink.
Why this matters
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